The expression and functions of toll-like receptors in atherosclerosis

Abstract

Inflammation drives atherosclerosis. Both immune and resident vascular cell types are involved in the development of atherosclerotic lesions. The phenotype and function of these cells are key in determining the development of lesions. Toll-like receptors are the most characterised innate immune receptors and are responsible for the recognition of exogenous conserved motifs on pathogens, and, potentially, some endogenous molecules. Both endogenous and exogenous TLR agonists may be present in atherosclerotic plaques. Engagement of toll-like receptors on immune and resident vascular cells can affect atherogenesis as signalling downstream of these receptors can elicit proinflammatory cytokine release, lipid uptake, and foam cell formation and activate cells of the adaptive immune system. In this paper, we will describe the expression of TLRs on immune and resident vascular cells, highlight the TLR ligands that may act through TLRs on these cells, and discuss the consequences of TLR activation in atherosclerosis.

Figure 1

Toll-like receptor expression in atherosclerotic lesions is cell-type specific. Endothelial cell activation leads to increased expression of adhesion molecules, promoting the infiltration of monocytes into the subendothelial space. Recruited monocytes differentiate into macrophages, ingest lipid and become foam cells that are retained within the lesion, promoting plaque growth. Smooth muscle cells proliferate and migrate into the intima where they form a fibrous plaque over the necrotic core of the lesion. In addition, myleloid dendritic cells, plasmacytoid dendritic cells and lymphocytes are observed in lesions. Both immune and resident vascular cells in atherosclerotic arteries express a variety of toll-like receptors or increase their expression during disease development. Each cell type expresses a specific combination which might dictate its ability to respond to exogenous or endogenous ligands and the consequences of such stimulation. Ligation of toll-like receptors on cells within atherosclerotic plaques can lead to numerous downstream effects including; promoting monocyte recruitment, activation of plaque cells, induction of foam cell formation and activation of adaptive immune responses, which can all affect lesion development.